Oral or injectable drugs are commonly used to treat various diseases and conditions. However, these therapeutic approaches result in systemic drug exposure that may be unnecessary or even undesirable. Further, most orally-administered drugs require at least daily dosing to maintain adequate drug levels. Even when targeted drug delivery is possible because of the accessible location of the tissue to be treated, it is still often difficult to attain adequate drug levels over an extended period of time for various reasons. Some of these difficulties are illustrated by treatments targeted to the eyes, ears, and nasal sinuses.
Ocular Tissues
The treatment of many ophthalmic diseases and post-operative conditions require frequent administration of drugs to the ocular tissues. Many medications must be applied topically to the eye and one common form of treatment is the use of drops or ointments. The topical formulation is administered by the patient or caregiver using an eye dropper or dispenser. However, a substantial disadvantage of this method of drug delivery is that the medication rapidly drains from the ocular surface into the lacrimal system through an opening in the eyelid called the punctum. Furthermore, the medication is rapidly diluted by the tears secreted by the lacrimal gland. This problem is further compounded by the patients themselves: one of the principal limitations of topical medication is poor patient compliance. The more often a patient is required to use medication, the less likely they will administer the proper dose at the proper time.
Thus, topical treatments do not provide a continuous, prolonged delivery of medication and the exact dosage achieved at the target tissue is unpredictable. Intermittent administration also is problematic because there is an initial overdosage followed by a rapid decrease in concentration due to dilution and lacrimal drainage to ineffective levels.
Another approach for achieving localized drug delivery involves the injection of drug directly under the conjunctiva or tenon's capsule, intra-camerally or intra-vitreally. Unfortunately, this approach may require periodic injections of drug to maintain an effective drug concentration at the target site and has many potential adverse effects.
Accordingly, there is a need for a sustained, controlled, delivery system for ophthalmic drugs.
Otic Tissues
Similar to ocular liquid treatments, the delivery of therapeutic agents in a controlled and effective manner to inner ear tissues is difficult, particularly when considering the tissue structures of the inner ear (e.g. those portions of the ear surrounded by the otic capsule bone and contained within the temporal bone which is the most dense bone tissue in the entire human body). The same delivery issues exist in connection with tissues leading into the inner ear (e.g. the round window membrane).
Conventional methods for delivery of therapeutic agents to the inner ear involve filling the middle ear with a solution or other carrier of the therapeutic agent. Although these methods may ultimately result in delivery of drug into the inner ear (e.g., by perfusion through the round window membrane), delivery of the therapeutic agent is generally not well controlled and/or use of the carrier materials may be associated with adverse side effects.
Thus, there is also a need for a sustained, controlled delivery system for otic agents.
Sinus (Nasal) Tissues
Similar to ocular and otic liquid treatments, there are issues regarding nasal treatments. Treatments for sinusitis include systemic antibiotics, but systemic administration of antibiotics, particularly over extended periods as may be required to treat sinusitis, can have undesirable effects on the flora of the digestive tract and reproductive system. Intranasal corticosteroid sprays and intranasal decongestant sprays and drops have also been used. However, the use of intranasal sprays and drops by most patients does not result in the drug actually entering the affected intranasal sinuses. Rather, such sprays and drops typically contact only tissues located within the nasal cavity.
Therefore, there is also a need for a sustained, controlled delivery systems for sinus (nasal) agents.
Drug Delivery Systems
Various methods have been developed to prolong drug exposure following a single dosing. For example, the drug may be formulated into a slow release formulation (see, for example, Langer (1998) NATURE 392, Supp. 5-10). In some of these systems the drug is conjugated with polymers that are degraded, for example, by proteolytic enzymes or by hydrolysis, to gradually release drug into the target site following administration. In another approach, drug is trapped throughout an insoluble matrix. Following administration, drug then is released via diffusion out of, or via erosion of, the matrix. Alternatively, drug can be encapsulated within a semi-permeable membrane or liposome. Following administration, the drug is released either by diffusion through the membrane or via breakdown of the membrane.
Specialized deliver systems for the eye, ear, and nasal sinuses have also been developed, and some of these are described below.
Ocular Delivery Systems
Several systems shown in U.S. patents describe large ocular inserts to continuously deliver active agents to the eye. Certain inserts disperse the drug and require removal of the carrier of the drug once the drug has been delivered. However, U.S. Pat. Nos. 3,845,201; 4,164,559 and 4,179,497 show various inserts in the form of large pellets which dispense drug over a period of time and eventually are completely eroded, and thus do not require removal after drug delivery.
U.S. Pat. No. 4,164,559 describes an ophthalmic drug delivery system comprising (a) an enzyme-extracted, chemically-modified collagen thin membrane carrier selected from the group consisting of esterified collagen and acylated collagen and having a pH in the range of 5.5-9.0 whereby the carrier is soluble in the tear fluid under physiologic conditions, and (b) an ophthalmically active drug incorporated into the carrier. U.S. Pat. No. 4,882,150 describes an ophthalmic drug delivery system, which includes at least one particle of bioerodible material, and a liquid or ointment carrier which includes ophthalmic drug to be delivered to the ocular area. The bioerodible material includes collagen. U.S. Pat. No. 5,512,301 describes collagen-containing sponges comprising an absorbable gelatin sponge, collagen, and an active ingredient and the use of the sponges in methods of enhancing wound healing of external and internal wounds. U.S. Pat. Nos. 6,197,934 and 6,448,378 describes collagen films which rapidly dissolve at 35° C., methods for preparing the collagen films, and their use for delivering a dose of therapeutic compound to a specific tissue site. U.S. Pat. No. 5,418,222 describes a multi-layered collagen film for use in controlled release of an active ingredient, said film comprising one or two rate controlling layers and one or more drug reservoir layers, said layers comprising non-fibrillar collagen and contacting each other in a stacked conformation such that a rate controlling layer is situated at one or both ends of the stack and contacts only one other layer, said other layer being a drug reservoir layer.
These inserts have certain advantages over liquid treatments in that a more predictable dosage is obtained because drug is continuously dispensed over a period of time without rapid washout. Thus, the unit ocular inserts provide predictable dosage over a period of time without the requirement of repeated applications as required with liquid treatments. However, the inserts described in these patents are reported to support drug release only over a period of time ranging from less than a day to about a week.
Various ocular drug delivery implants have also been described in an effort to improve and prolong drug delivery. For example, U.S. Pat. No. 3,949,750 discloses a punctual plug made of a tissue-tolerable, readily sterilizable material, such as Teflon, HEMA, hydrophilic polymer, methyl methacrylate, silicone, stainless steel or other inert metal material. The punctual plug may be impregnated with ophthalmic medication or may contain a reservoir of the ophthalmic drug. U.S. Pat. No. 5,053,030 similarly discloses an intracanalicular implant. U.S. Pat. No. 5,469,867 discloses a method of blocking a channel, such as the lacrimal canaliculus by injecting a heated flowable polymer into the channel and allowing it to cool and solidify. The polymer may be combined with a biologically active substance that could leach out of the solid punctum once it has formed in the channel. WO 99/37260 discloses a punctual plug made of a moisture absorbing material, which is not soluble in water, such as a modified HEMA. An inflammation inhibitor, such as heparin, may be added to the material from which the punctual plug is made. U.S. Pat. No. 6,196,993 discloses a punctual plug containing glaucoma medication. The medication is contained in a reservoir within the plug that is in fluid communication with a pore through which the medication is released onto the eye. WO 2006/031658 discloses lacrimal canalicular inserts including a polymer component and a therapeutic component. Similarly, U.S. Pub. No. 2006/0020248 discloses an ophthalmological device for lacrimal insertion that includes a reservoir for a medication. U.S. Pub. No. 2004/0013704 discloses solid or semi-solid implant compositions lacking polymeric ingredients. These implant compositions are made of lipophilic compounds and may contain an ophthalmic drug. They may be implanted anywhere in the eye including the punctum or lacrimal canaliculous. U.S. Pub. No. 2005/0232972 discloses ocular implants to which active agents have been applied to at least one surface. In one embodiment, a porous or absorbent material can be used to make up the entire plug or implant which can be saturated with the active agent. WO 2004/066980 discloses a device for delivering a carbonic anhydrase inhibitor (CAI) to the eye over an extended period of time. In one embodiment, the device has an inner CAI-containing core and an outer polymeric layer. The outer layer may be permeable, semi-permeable, or impermeable to the drug. Where the outer layer is impermeable to the drug, it may have one or more openings to permit diffusion of the CAI. U.S. Pub. No. 2003/0143280 discloses the use of biodegradable polymer capsules for treating ophthalmic disorder including dry eye and glaucoma. The capsules are made of any biodegradable, biocompatible polymer and may contain a treating agent.
Otic Delivery Systems
Otic delivery systems that have been described use naturally-occurring materials such as gelatin (e.g., Gelfoam, see, e.g., Silverstein Ann Otol Rhinol Laryngol Suppl. 112:44-8. (1984); Lundman et al. Otolaryngol 112:524 (1992); Nedzelski et al. Am. J. Otol. 14:278-82 (1993); Silverstein et al. Ear Nose Throat J 75:468-88 (1996); Ramsay et al. Otolaryngol. 116:39 (1996); Ruan et al. Hear Res 114:169 (1997); Wanamaker et al. Am. J. Otology 19:170 (1998); Arriaga et al. Laryngoscope 108:1682-5 (1998); and Husmann et al. Hear Res 125:109 (1998)), hyaluronan or hyaluronic acid (see, e.g., WO 97/38698; Silverstein et al. Am J Otol. 19(2):196-201 (1998)), or fibrin glue or other fibrin-based vehicle (see, e.g., Balough et al. Otolaryngol. Head Neck Surg. 119:427-31 (1998); Park et al. Laryngoscope 107:1378-81 (1997)).
Although these methods may ultimately result in delivery of drug into the inner ear (e.g., by perfusion through the round window membrane), delivery of the therapeutic agent is generally not well controlled and/or use of the carrier materials may be associated with adverse side effects. For example, use of gelatin-based materials such as Gelfoam can cause fibrosis in the middle ear cavity (see, e.g., Laurent et al. Am. J. Otolaryngol 7(3):181-6 (1986); Liening et al. Otolaryngol. Head Neck Surg. 116:454-7 (1997)). Furthermore, naturally-occurring carrier materials generally do not retain their shape following introduction into the ear (e.g., the materials are naturally viscous or become more liquid upon introduction into the ear). The changes in the shape of the carrier materials make it extremely difficult to completely retrieve the materials from the site of introduction if such should be desired (e.g., to terminate therapy). It may even prevent delivery of additional therapeutic agents in subsequent treatments (see, e.g., Silverstein et al. Am J. Otol 18:586-9 (1997), describing how gelfoam becomes paste-like and prevents future injections of this material from reaching the inner ear fluids).
Sinus (Nasal) Delivery Systems
The introduction of drugs directly into the sinuses has been proposed by others, but has not become a widely used treatment technique. For example, U.S. Pub. 2004/0116958A1 (Gopferich et al.) describes a tubular sheath or “spacer” formed of biodegradable or non-biodegradable polymer that, prior to insertion in the patient's body, is loaded with a controlled amount of an active substance, such as a corticosteroid or anti-proliferative agent. Surgery is performed to create a fenestration in a frontal sinus and the sheath is inserted into the fenestration. In some embodiments, the sheath is formed of multiple layers of polymeric material, one or more of which is/are loaded with the active substance and one or more of which is/are free of the active substance. In other embodiments, the sheath has a “hollow body” which forms a reservoir system wherein the active substance is contained and a membrane which controls the release of the active substance from the reservoir.
Also, Min, Yang-Gi, et al., “Mucociliary Activity and Histopathology of Sinus Mucosa in Experimental Maxilary Sinusitis: A Comparison of Systemic Administration of Antibiotic and Antibiotic Delivery by Polylactic Acid Polymer,” Laryngoscope, 105:835-842 (August 1995) describes experiments wherein experimental sinusitis was induced in three groups of rabbits by “pasting” the natural sinus ostia, forming an incision and small bore hole made in the anterior wall of the sinus, introducing pathogenic microbes through the bore hole and then closing the incision. Five days after introduction of the pathogenic microbes, the natural sinus ostia were reopened and the rabbits were divided into three (3) groups. Group 1 (control) received no treatment. Group 2 received repeated intramuscular injections of ampicillin. In the animals of Group 3, 1.5 cm×1.5 cm sheets of polylactic acid polymer (PLA) film containing ampicillin (0.326 mg/sheet) were rolled up and inserted through the natural ostia into the infected sinuses. Thereafter, measurements of mucocilliary transport speed were made and the tissues lining the affected sinuses were examined histopathologically. The authors concluded that the therapeutic effect observed in the animals that had received intrasinus implants of PLA/Ampicillin film (Group 3) was significantly better that that observed in the untreated control animals (Group 1) or those that has received repeated intramuscular doses of ampicillin (Group 2).
U.S. Pat. No. 3,948,254 (Zaffaroni), incorporated by reference, describes implantable drug delivery devices comprising a drug reservoir surrounded by a microporous wall. The reservoir may be formed of any of a variety of solid drug carriers that are permeable to passage of the drug. Zaffaroni describes a number of applications for the implantable drug delivery devices including placement in a nasal passage. That reference also discusses zero order release and how such release can be determined.
Other publications have also reported that introduction of drugs directly into the paranasal sinuses is effective in the treatment of sinusitis. See, Tarasov, D. I., et al., Vestn Otorinolaringol. Vol. 6, Pages 45-7 (1978). Also, R. Deutschmann, et al., Stomat. DDR 26 (1976), 585-592 describes the placement of a resorbable drug delivery depot within the maxillary sinus for the purposes of eluting drugs, specifically chloramphenicol. In this clinical series a water soluble gelatin was used as carrier that was mixed with the drug prior to application and introduced as a mass into the sinus. Since the substance had little mechanical integrity and dissolved in a relatively short timeframe, to achieve a therapeutic effect, the author suggested that it must be instilled every 2 to 3 days. U.S. Pat. No. 6,398,758 to Jacobsen et al. describes a hollow cylindrical sponge loaded with drug and pressed against a blood vessel wall. This allows the drug to contact the wall while sustaining blood flow within the center of the lumen. Further, a skin is provided to direct the drug into the walls of the blood vessel and prevent drug from flowing into the lumen. While sponges loaded with drug at the time of their application do permit some degree of sustained release, the time required to load them also correlates closely with the time over which they will elute substance. Thus, if delivery is required for a longer period of time additional mechanisms must be employed to regulate their release.
Many of the devices described above are reservoir-type drug-delivery devices that contain a receptacle or chamber for storing the drug. There are drawbacks to reservoir drug delivery devices in that they are difficult to manufacture, difficult to achieve drug content uniformity (i.e., device to device reproducibility, particularly with small ocular devices), and they carry the risk of a “dose dump” if they are punctured.
There are also several examples in the patent literature where various sustained release mechanisms have generally been proposed using systems with pre-incorporated drugs into matrices or polymers. These include U.S. Pat. No. 3,948,254 (Zafferoni), US 2003/0185872A2 (Kochinke), WO 92/15286 (Shikani), and U.S. Pat. No. 5,512,055 (Domb, et al.). In general, these references discuss various materials and structures that may be used to construct sustained drug delivery vehicles and provide an overview of the state of sustained drug delivery art. None of these references, however, describes specific methods, means, or structures which would permit them to be easily adapted for the intended uses targeted in this application.
In matrix drug delivery devices the drug is dispersed throughout a polymeric matrix and is released as it dissolves or diffuses out of the matrix. Matrix devices have an advantage over reservoir devices in that they are not subject to a dose dump if punctured. A disadvantage of matrix devices is that it can be difficult to achieve zero-order drug release kinetics. Zero-order drug release or near zero-order drug release is desirable because the rate of drug release is independent of the initial concentration of the drug, thus the drug can be released at therapeutic levels over a sustained period of time. The manufacture of matrix devices can also present difficulties when the drug and the polymer are processed and extruded at elevated temperature and/or pressure as this may reduce the activity of the drug.
DeVore has previously described several collagen-based drug delivery systems, but those systems provided either rapid release of the therapeutic component or provided an initial bolus release of the therapeutic agent followed by a time declining release of the therapeutic agent. Such compositions did not provide desired zero order release, or involved in vivo polymerizing gels. For example, WO 00/47114 describes an injectable fibrillar collagen solution comprising bone morphogenic proteins that polymerizes in situ to form a matrix, but in this system 50% of the drug was released within the first 24 hours and the longest period of release measured was 400 hours. WO 00/47130 similarly describes collagen solutions that convert to gels following in vivo placement. The solutions may be used for delivering cells and or drugs to a tissue by crosslinking them to the collagen using ultraviolet radiation. When release of the drug acyclovir was tested in this in vivo polymerizing gel system, release was detected at the longest time point measured, 28 days. In an abstract (DeVore et al., Abstract 5126-B524, ARVO, 2006), propose the use of this system to deliver sustained release of growth factors and other agents for treatment of retinal disorders for up to 2 months, but no details were given. In ARVO abstract 480-B454 (Invest Ophthalmol Vis Sci 2005; 46:) release and diffusion of dexamethasone from collagen gels and films through human scleral tissue was measured for a 24 hour period. No long-term release was evaluated. In ARVO abstract 1816-D686 (Invest Ophthalmol Vis Sci 2008; 49: E-Abstract 1816) release of POT-4 (a strong complement inhibitor peptide) from collagen gel was bi-phasic with an initial burst followed by sustained release.
The collagen-based drug delivery constructs of the present invention address deficiencies in the art by providing matrices that achieve zero-order or near zero-order drug-release kinetics typically associated with reservoir devices, but without the risk of dose dumping and the manufacturing difficulties of reservoir devices. Further, while the collagen-based drug delivery constructs are illustrated in the context of ophthalmic, otic, and sinus drug delivery, those uses are illustrative only as the collagen-based drug delivery constructs can be used anywhere in the body that prolonged delivery of a precise dose of drug or other agent is needed.